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- Title
MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.
- Authors
Ding, X.; Mohd, A. B.; Huang, Z.; Baba, T.; Bernardini, M. Q.; Lyerly, H. K.; Berchuck, A.; Murphy, S. K.; Buermeyer, A. B.; Devi, G. R.
- Abstract
<bold>Background: </bold>The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms.<bold>Methods: </bold>In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III-IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status.<bold>Results: </bold>The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells.<bold>Conclusion: </bold>These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.
- Subjects
OVARIAN cancer; CELL death; APOPTOSIS; CANCER patients; CELL lines; GENE expression; CARRIER proteins; CISPLATIN; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; OVARIAN tumors; PROTEINS; PURINES; RESEARCH; RESEARCH funding; RNA; TRANSFERASES; EVALUATION research; NUCLEAR proteins; CHEMICAL inhibitors
- Publication
British Journal of Cancer, 2009, Vol 101, Issue 2, p269
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/sj.bjc.6605180